A complementary drug to combat Alzheimer's disease could target a specific part of the nerve cell protein tau. This is the finding of research from the University of Gothenburg, which also offers a better way to measure the effect of treatment among patients.
Researchers from the University of Gothenburg, together with colleagues from the University of Pittsburgh in the US, published their findings in the journal Nature Medicine.
The study provides insights into what happens during the earliest phase when the protein tau is transformed into thread-like strands (fibrils) in the nerve cells. This is one of the processes in Alzheimer's disease and occurs alongside the formation of amyloid plaques. In healthy individuals, the protein tau stabilizes the tubular building blocks (microtubules) that make up the long projections of the nerve cells.
During the development of Alzheimer's disease, tau undergoes pathological changes. First, tau forms small, soluble aggregates that are secreted from the nerve cells and are thought to be able to spread these changes to other nerve cells. The protein is then converted into larger, harmful, thread-like strands in the nerve cells.
Tohidul Islam, a researcher at the University of Gothenburg's Sahlgrenska Academy, is one of the study's lead authors.
"In our study, we look at how tau is modified, which leads it to form its soluble clumps. We found that changes in two specific amino acids, serine-262 and serine-356, happen before these thread-like fibrils start to form in the nerve cells," says Tohidul Islam
Complementary drugs
Alzheimer's research has made significant advances around the world in recent years. Many countries - although not yet in the EU - have approved the Alzheimer's drug lecanemab. An American drug donanemab is also being developed. Both drugs target the process that is deemed to be the most important in the progression of the disease: the accumulation of the protein beta-amyloid in the brain.
"Our hypothesis is that tau in its soluble form helps the disease process to spread in the brain," says Kaj Blennow, a University of Gothenburg professor and one of the senior researchers behind the study. "If researchers want to develop drugs in the future to combat the tau pathology as a complement to drugs that target the amyloid plaque, we now know which regions are of interest to focus on."
Measuring the effect of treatment
The drug lecanemab was first introduced almost two years ago and has demonstrated good results in terms of reducing the amyloid plaque in the brain among patients at an early stage of Alzheimer's disease. However, it is impossible to know with any degree of certainty what the long-term results will be. The findings regarding the soluble phosphorylated small aggregates of the protein tau also offer a new opportunity to demonstrate the protein changes before the larger fibrils form in the nerve cells. The study therefore provides a biomarker that can be directly linked to the amount of tau pathology in patients' brains.
Article:: Phosphorylation at serine-262 and serine-356 detects early-stage pre-tangle soluble tau assemblies in Alzheimer's disease; Nature Medicine.
